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BMJ Open May 2024DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in...
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children (MARVEL- PIC): protocol for a national randomised controlled trial of pharmacogenomics implementation.
INTRODUCTION
DNA-informed prescribing (termed pharmacogenomics, PGx) is the epitome of personalised medicine. Despite international guidelines existing, its implementation in paediatric oncology remains sparse.
METHODS AND ANALYSIS
Minimising Adverse Drug Reactions and Verifying Economic Legitimacy-Pharmacogenomics Implementation in Children is a national prospective, multicentre, randomised controlled trial assessing the impact of pre-emptive PGx testing for actionable PGx variants on adverse drug reaction (ADR) incidence in patients with a new cancer diagnosis or proceeding to haematopoetic stem cell transplant. All ADRs will be prospectively collected by surveys completed by parents/patients using the National Cancer Institute Pediatric Patient Reported [Ped-PRO]-Common Terminology Criteria for Adverse Events (CTCAE) (weeks 1, 6 and 12). Pharmacist will assess for causality and severity in semistructured interviews using the CTCAE and Liverpool Causality Assessment Tool. The primary outcome is a reduction in ADRs among patients with actionable PGx variants, where an ADR will be considered as any CTCAE grade 2 and above for non-haematological toxicities and any CTCAE grade 3 and above for haematological toxicities Cost-effectiveness of pre-emptive PGx (secondary outcome) will be compared with standard of care using hospital inpatient and outpatient data along with the validated Childhood Health Utility 9D Instrument. Power and statistics considerations: A sample size of 440 patients (220 per arm) will provide 80% power to detect a 24% relative risk reduction in the primary endpoint of ADRs (two-sided α=5%, 80% vs 61%), allowing for 10% drop-out.
ETHICS AND DISSEMINATION
The ethics approval of the trial has been obtained from the Royal Children's Hospital Ethics Committee (HREC/89083/RCHM-2022). The ethics committee of each participating centres nationally has undertaken an assessment of the protocol and governance submission.
TRIAL REGISTRATION NUMBER
NCT05667766.
Topics: Humans; Child; Drug-Related Side Effects and Adverse Reactions; Pharmacogenetics; Prospective Studies; Randomized Controlled Trials as Topic; Neoplasms; Multicenter Studies as Topic; Precision Medicine; Hematopoietic Stem Cell Transplantation
PubMed: 38760050
DOI: 10.1136/bmjopen-2024-085115 -
BMJ Open May 2024(STEPS) is a digital application (app) designed to help parents manage behaviour of their children who are referred to mental health services and are waiting for an...
INTRODUCTION
(STEPS) is a digital application (app) designed to help parents manage behaviour of their children who are referred to mental health services and are waiting for an assessment or treatment. STEPS is currently being evaluated in the Online Parent Training for the Initial Management of Attention-Deficit/Hyperactivity Disorder randomised controlled trial. Alongside the examination of STEPS' clinical and cost-effectiveness, we are conducting a process evaluation to better understand the contextual factors that may influence study outcomes. The purpose of this protocol is to describe the aims, objectives and methodology of the process evaluation prior to it taking place to add to the fidelity and rigour of the trial process and outcomes. Our goal is to adapt STEPS to optimise its benefits in future applications.
METHODS
In line with the Medical Research Council guidelines for evaluating complex interventions, the process evaluation will adopt a mixed method design using qualitative data collected from clinicians and parent interviews and app usage data from participants assigned to the intervention arm.
ANALYSIS
Qualitative data from semistructured interviews and free text box responses included in trial questionnaires will be analysed thematically using framework analysis to better understand how parents use STEPS, how it works and key factors that could aid or hinder its effective implementation in routine clinical practice.
ETHICS
The application for ethical approval for the study was submitted to the North West-Liverpool Central Research Ethics Committee and received a favourable opinion on further information on 26 November 2021, reference number 21/NW/0319.
DISSEMINATION
The process evaluation aims to explore how a digital app might support parents in managing their child's behaviour. Implications for policy and research will be explored and the clinical implications of offering the app to a wider audience to address the lack of support to parents as highlighted in this paper. We plan to publish findings in international, peer-reviewed journals as well as present at conferences.
TRIAL REGISTRATION NUMBER
The trial has been prospectively registered on 18 November 2021; ISRCTN816523503. https://www.isrctn.com/ISRCTN16523503.
Topics: Humans; Parenting; Parents; Child; Attention Deficit Disorder with Hyperactivity; Randomized Controlled Trials as Topic; Mobile Applications; Research Design
PubMed: 38760045
DOI: 10.1136/bmjopen-2023-081563 -
BMJ Open May 2024Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality. Often little is known... (Observational Study)
Observational Study
INTRODUCTION
Around 2000 children are born in the UK per year with a neurodevelopmental genetic syndrome with significantly increased morbidity and mortality. Often little is known about expected growth and phenotypes in these children. Parents have responded by setting up social media groups to generate data themselves. Given the significant clinical evidence gaps, this research will attempt to identify growth patterns, developmental profiles and phenotypes, providing data on long-term medical and educational outcomes. This will guide clinicians when to investigate, monitor or treat symptoms and when to search for additional or alternative diagnoses.
METHODS AND ANALYSIS
This is an observational, multicentre cohort study recruiting between March 2023 and February 2026. Children aged 6 months up to 16 years with a pathogenic or likely pathogenic variant in a specified gene will be eligible. Children will be identified through the National Health Service and via self-recruitment. Parents or carers will complete a questionnaire at baseline and again 1 year after recruitment. The named clinician (in most cases a clinical geneticist) will complete a clinical proforma which will provide data from their most recent clinical assessment. Qualitative interviews will be undertaken with a subset of parents partway through the study. Growth and developmental milestone curves will be generated through the DECIPHER website (https://deciphergenomics.org) where 5 or more children have the same genetic syndrome (at least 10 groups expected).
ETHICS AND DISSEMINATION
The results will be presented at national and international conferences concerning the care of children with genetic syndromes. Results will also be submitted for peer review and publication.
Topics: Humans; Rare Diseases; Child; Child, Preschool; United Kingdom; Infant; Adolescent; Research Design; Female; Male; Observational Studies as Topic; Neurodevelopmental Disorders; Cohort Studies; Multicenter Studies as Topic; Genetic Diseases, Inborn; Quality Improvement; Parents
PubMed: 38760043
DOI: 10.1136/bmjopen-2024-085237 -
Medicine May 2024Incretin-based drugs, a class of Antidiabetic medications (ADMs) used in the treatment of type 2 diabetes, may affect the incidence of prostate cancer (PCa). But... (Meta-Analysis)
Meta-Analysis
Incretin-based drugs, a class of Antidiabetic medications (ADMs) used in the treatment of type 2 diabetes, may affect the incidence of prostate cancer (PCa). But real-world evidence for this possible effect is lacking. Therefore, the aim of this study is to assess the effect of incretin-based drugs on the incidence of PCa, including glucagon-like peptide-1 (GLP-1) receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors. We searched PubMed, Embase, and Cochrane Library databases for eligible studies through September 2023. Two independent reviewers performed screening and data extraction. We used the Cochrane Handbook for Systematic Reviews and the Newcastle-Ottawa Scale (NOS) to assess the quality of included randomized controlled trials (RCTs) and cohort studies. We did a meta-analysis of available trial data to calculate overall risk ratios (RRs) for PCa. A total of 1238 articles were identified in our search. After screening for eligibility, 7 high-quality studies met the criteria for meta-analysis, including 2 RCTs and 5 cohort studies, with a total of 1165,738 patients. Compared with the control group, we found that incretin-based drugs reduced the relative risk of PCa by 35% (95% confidence interval (CI), 0.17-0.49; P = .0006). In subgroup analysis, the RR values for GLP-1 receptor agonists and DPP-4 inhibitors were 62% (95% CI, 0.45-0.85; P = .003) and 72% (95% CI, 0.46-1.12; P = .14), respectively. Incretin-based drugs are associated with lower incidence of prostate cancer and may have a preventive effect on prostate cancer in patients with type 2 diabetes.
Topics: Humans; Male; Prostatic Neoplasms; Diabetes Mellitus, Type 2; Incidence; Incretins; Hypoglycemic Agents; Dipeptidyl-Peptidase IV Inhibitors
PubMed: 38758855
DOI: 10.1097/MD.0000000000038018 -
PloS One 2024Insulin resistance is a common pathophysiology in patients with type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Thus, screening...
Insulin resistance is a common pathophysiology in patients with type 2 diabetes mellitus, cardiovascular disease, and non-alcoholic fatty liver disease. Thus, screening for the risk of insulin resistance is important to prevent disease progression. We evaluated the alanine aminotransferase/aspartate aminotransferase (ALT/AST) ratio to predict insulin resistance in the general population, regardless of comorbidities. Datasets from the 2015, 2019, and 2020 Korea National Health and Nutrition Examination Surveys were used, and the following four indices were implemented to indicate insulin resistance: fasting serum glucose, insulin, homeostatic model assessment for insulin resistance (HOMA-IR), and β-cell function. We analyzed the degree of association between the liver enzyme profile and insulin resistance indices using Pearson's correlation coefficient and determined the associations using linear or logistic regression analysis. Accordingly, ALT levels in both sexes were positively and consistently correlated with the four aforementioned insulin resistance indices in stratification analyses based on diabetes, dyslipidemia, alcohol consumption, and obesity status. In multivariate linear regression, when comparing with ALT levels, the ALT/AST ratio exhibited superior predictive performance for fasting serum glucose and HOMA-β in Korean men and improved outcomes for all insulin resistance indices in Korean women. In this analysis that included a large community-based population, the ALT/AST ratio was a more useful predictive marker than the HOMA-IR. Regarding the predicted presence or absence of insulin resistance, the ALT/AST ratio could better predict HOMA-IR than the ALT level alone in Koreans. A simple, precise marker that represents the ALT/AST ratio could be a practical method to screen for insulin resistance in the general population, regardless of diabetes mellitus, alcohol intake, and sex.
Topics: Humans; Insulin Resistance; Male; Female; Republic of Korea; Alanine Transaminase; Middle Aged; Cross-Sectional Studies; Aspartate Aminotransferases; Adult; Blood Glucose; Diabetes Mellitus, Type 2; Nutrition Surveys; Cohort Studies; Aged
PubMed: 38758828
DOI: 10.1371/journal.pone.0303333 -
Oncotarget May 2024GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15%...
GZ17-6.02 has undergone phase I evaluation in patients with solid tumors (NCT03775525). The RP2D is 375 mg PO BID, with an uveal melanoma patient exhibiting a 15% reduction in tumor mass for 5 months at this dose. Studies in this manuscript have defined the biology of GZ17-6.02 in PDX isolates of uveal melanoma cells. GZ17-6.02 killed uveal melanoma cells through multiple convergent signals including enhanced ATM-AMPK-mTORC1 activity, inactivation of YAP/TAZ and inactivation of eIF2α. GZ17-6.02 significantly enhanced the expression of BAP1, predictive to reduce metastasis, and reduced the levels of ERBB family RTKs, predicted to reduce growth. GZ17-6.02 interacted with doxorubicin or ERBB family inhibitors to significantly enhance tumor cell killing which was associated with greater levels of autophagosome formation and autophagic flux. Knock down of Beclin1, ATG5 or eIF2α were more protective than knock down of ATM, AMPKα, CD95 or FADD, however, over-expression of FLIP-s provided greater protection compared to knock down of CD95 or FADD. Expression of activated forms of mTOR and STAT3 significantly reduced tumor cell killing. GZ17-6.02 reduced the expression of PD-L1 in uveal melanoma cells to a similar extent as observed in cutaneous melanoma cells whereas it was less effective at enhancing the levels of MHCA. The components of GZ17-6.02 were detected in tumors using a syngeneic tumor model. Our data support future testing GZ17-6.02 in uveal melanoma as a single agent, in combination with ERBB family inhibitors, in combination with cytotoxic drugs, or with an anti-PD1 immunotherapy.
Topics: Melanoma; Uveal Neoplasms; Humans; Animals; Mice; Xenograft Model Antitumor Assays; Cell Line, Tumor; Signal Transduction; Autophagy; Ubiquitin Thiolesterase; Doxorubicin; Antineoplastic Agents; TOR Serine-Threonine Kinases; Tumor Suppressor Proteins
PubMed: 38758815
DOI: 10.18632/oncotarget.28586 -
Science Advances May 2024Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated...
Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine-635 was mutated to glutamine (K635Q). Male mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis, consistent with nonalcoholic fatty liver disease (NAFLD). RNA sequencing analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD. Fasted mouse livers showed increased fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), both associated with NAFLD, and increased carbohydrate response element-binding protein binding to and enhancer regions. Last, liver lipidomics showed elevated ceramide, lysophosphatidylethanolamine, and lysophosphatidylcholine, all associated with NAFLD. Thus, we propose that ACSS1-K635-Ac dysregulation leads to aberrant lipid metabolism, cellular senescence, and NAFLD.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Mice; Cellular Senescence; Acetylation; Mitochondria; Stearoyl-CoA Desaturase; Male; Acetate-CoA Ligase; Gene Knock-In Techniques; Liver; Lipid Metabolism; Sirtuin 3; Disease Models, Animal; Coenzyme A Ligases; Fatty Acid Synthase, Type I
PubMed: 38758779
DOI: 10.1126/sciadv.adj5942 -
PloS One 2024The interaction between SARS-CoV-2 non-structural protein Nsp9 and the nanobody 2NSP90 was investigated by NMR spectroscopy using the paramagnetic perturbation...
The interaction between SARS-CoV-2 non-structural protein Nsp9 and the nanobody 2NSP90 was investigated by NMR spectroscopy using the paramagnetic perturbation methodology PENELOP (Paramagnetic Equilibrium vs Nonequilibrium magnetization Enhancement or LOss Perturbation). The Nsp9 monomer is an essential component of the replication and transcription complex (RTC) that reproduces the viral gRNA for subsequent propagation. Therefore preventing Nsp9 recruitment in RTC would represent an efficient antiviral strategy that could be applied to different coronaviruses, given the Nsp9 relative invariance. The NMR results were consistent with a previous characterization suggesting a 4:4 Nsp9-to-nanobody stoichiometry with the occurrence of two epitope pairs on each of the Nsp9 units that establish the inter-dimer contacts of Nsp9 tetramer. The oligomerization state of Nsp9 was also analyzed by molecular dynamics simulations and both dimers and tetramers resulted plausible. A different distribution of the mapped epitopes on the tetramer surface with respect to the former 4:4 complex could also be possible, as well as different stoichiometries of the Nsp9-nanobody assemblies such as the 2:2 stoichiometry suggested by the recent crystal structure of the Nsp9 complex with 2NSP23 (PDB ID: 8dqu), a nanobody exhibiting essentially the same affinity as 2NSP90. The experimental NMR evidence, however, ruled out the occurrence in liquid state of the relevant Nsp9 conformational change observed in the same crystal structure.
Topics: Viral Nonstructural Proteins; Single-Domain Antibodies; SARS-CoV-2; Molecular Dynamics Simulation; Epitopes; Humans; Magnetic Resonance Spectroscopy; Protein Binding; Protein Multimerization; COVID-19; RNA-Binding Proteins
PubMed: 38758765
DOI: 10.1371/journal.pone.0303839 -
JAMA Health Forum May 2024Since the full-scale Russian invasion, hospitals in Ukraine have been compelled to close or operate at reduced capacity due to inadequate supplies, damage, or... (Comparative Study)
Comparative Study
IMPORTANCE
Since the full-scale Russian invasion, hospitals in Ukraine have been compelled to close or operate at reduced capacity due to inadequate supplies, damage, or destruction caused by war.
OBJECTIVE
To analyze hospital services in Ukraine during the period before and after the Russian invasion.
DESIGN, SETTING, AND PARTICIPANTS
Of the 450 hospitals currently functioning in Ukraine, a cross-sectional survey was carried out with the participation of 74 hospitals from 12 oblasts. Hospital administrators responded to an online survey with questions on the use of hospital services. Data were abstracted from hospital databases for the prewar period (before February 23, 2022) and during the war (February 23, 2022, to May 30, 2023).
MAIN OUTCOMES AND MEASURES
Hospital services (including emergency services, preventive services, screenings, laboratory tests, obstetrics, telehealth, pharmacy, and rehabilitation services) were compared during the prewar and war periods.
RESULTS
Of 450 Ukrainian hospitals in operation, 74 hospitals (16.0%) across 12 oblasts provided data for the current analyses. During the war, daily emergency admissions increased to 2830, compared with 2773 before the war. At the same time, hospitals reported reduced laboratory testing (72 [97%] vs 63 [85%]), tobacco education (52 [70%] vs 36 [49%]), cancer screening (49 [66%] vs 37 [50%]), gynecological services (43 [58%] vs 32 [43%]), rehabilitation services (37 [50%] vs 27 [36%]), pharmacy services (36 [49%] vs 27 [36%]), and telehealth programs (33 [45%] vs 21 [28%]). Hospitals reported additional difficulties during the war, including disruptions in the supply chain for essential equipment and pharmaceuticals, shortages of laboratory test kits, delays in the delivery of crucial medications, and problems around appropriate medication storage due to power outages.
CONCLUSIONS AND RELEVANCE
The ongoing war has inflicted profound devastation on Ukraine's hospitals. The findings of this cross-sectional survey offer valuable insights into the formidable challenges that hospitals confront in war-affected regions and underscore the pressing necessity for bolstering support to sustain and enhance hospital services during wartime.
Topics: Ukraine; Humans; Cross-Sectional Studies; Russia; Hospitals; Armed Conflicts
PubMed: 38758566
DOI: 10.1001/jamahealthforum.2024.0901 -
Microbiology Spectrum May 2024NO1 is a plant biomass-degrading ascomycete with a propensity to target the most recalcitrant components of lignocellulose. Here we applied proteomics and...
NO1 is a plant biomass-degrading ascomycete with a propensity to target the most recalcitrant components of lignocellulose. Here we applied proteomics and activity-based protein profiling (ABPP) to investigate the ability of NO1 to tailor its secretome for growth on different lignocellulosic substrates. Proteomic analysis of soluble and insoluble culture fractions following the growth of NO1 on six lignocellulosic substrates highlights the adaptability of the response of the NO1 secretome to different substrates. Differences in protein abundance profiles were maintained and observed across substrates after bioinformatic filtering of the data to remove intracellular protein contamination to identify the components of the secretome more accurately. These differences across substrates extended to carbohydrate-active enzymes (CAZymes) at both class and family levels. Investigation of abundant activities in the secretomes for each substrate revealed similar variation but also a high abundance of "unknown" proteins in all conditions investigated. Fluorescence-based and chemical proteomic ABPP of secreted cellulases, xylanases, and β-glucosidases applied to secretomes from multiple growth substrates for the first time confirmed highly adaptive time- and substrate-dependent glycoside hydrolase production by this fungus. NO1 is a promising new candidate for the identification of enzymes suited to the degradation of recalcitrant lignocellulosic feedstocks. The investigation of proteomes from the biomass bound and culture supernatant fractions provides a more complete picture of a fungal lignocellulose-degrading response. An in-depth understanding of this varied response will enhance efforts toward the development of tailored enzyme systems for use in biorefining.IMPORTANCEThe ability of the lignocellulose-degrading fungus NO1 to tailor its secreted enzymes to different sources of plant biomass was revealed here. Through a combination of proteomic, bioinformatic, and fluorescent labeling techniques, remarkable variation was demonstrated in the secreted enzyme response for this ascomycete when grown on multiple lignocellulosic substrates. The maintenance of this variation over time when exploring hydrolytic polysaccharide-active enzymes through fluorescent labeling, suggests that this variation results from an actively tailored secretome response based on substrate. Understanding the tailored secretomes of wood-degrading fungi, especially from underexplored and poorly represented families, will be important for the development of effective substrate-tailored treatments for the conversion and valorization of lignocellulose.
PubMed: 38757984
DOI: 10.1128/spectrum.03943-23